CN101429201A - Lemon acid berbamine salt, preparation method and application thereof - Google Patents

Abstract

The invention provides a berbamine citrate salt, which uses berbamine free base as a raw material, and at room temperature, replaces the currently commonly used inorganic acid with an edible strong organic acid to perform a salt-forming reaction in a certain proportion to obtain citric acid Berbamine citrate. The berbamine citrate provided by the present invention not only has obvious killing effect on various blood tumor cells such as human leukemia, multiple myeloma and lymphoma cultured in vitro, but also has a significant effect on the growth of human blood tumor cells in nude mice. Inhibitory effect, while the same concentration of berbamine citrate has no obvious effect on the growth of normal human cells, and has no obvious toxic and side effects on nude mice; and can be composed of one or more other known antitumor drugs with optional therapeutically effective doses The pharmaceutical composition achieves synergistic effect. Therefore, the berbamine citrate salt provided by the invention can be used in the preparation of medicines for treating hematological neoplastic diseases.

Description

Berbamine citrate and its preparation method and application

technical field

The invention belongs to the field of chemistry, and relates to berbamine citrate and its preparation, as well as pharmaceutical combinations containing them and their application in preparation and treatment of hematological tumor diseases.

Background technique

According to the report of the World Health Organization: in 2007, about 25 million people in the world suffered from various cancers, and 7.9 million people died of these cancers (accounting for about 13% of all deaths). Cancer deaths are projected to continue to increase worldwide, with an estimated 12 million deaths from cancer in 2030. Cancer claimed nearly 1.8 million lives in China in 2006, about 300,000 more than in 2005. The 2006 Statistical Bulletin on the Development of China's Health Care, produced by the Health Statistics Center of the Ministry of Health, indicated that cancer "topped the list" for the first time among the causes of death among urban and rural residents in 2006. Among them, the cancer mortality rates of urban and rural residents increased by 14.76% and 21.57% respectively compared with 2005. That is to say, 834,000 urban residents and 960,000 rural residents died of cancer last year, accounting for almost a quarter of the total death toll throughout the year. Cancer has become the number one killer of human health. Unfortunately, the currently commonly used drugs cannot effectively control and treat these cancers, so it is of great significance to study new and better drugs to prevent and treat these cancers.

Berbamine is a bisbenzylisoquinoline alkaloid. Some literatures have reported that berbamine can induce apoptosis of some leukemia cells and other tumor cells. As reported in the previous research literature of the inventor of the present invention, in the in vitro culture system, berbamine hydrochloride can induce the apoptosis of human K562, Jurkat, HL-60, NB-4 leukemia cells, and inhibit the growth of leukemia cells [Xu R, et al .Leukemia Research.2006,30:17-23; Sun JR, et al.Zhonghua Yi Xue Za Zhi.2006;86:2246-51; Zhao XY, et al.Chin Med J(Engl).2007;120:802 -6]. It has also been reported in literature that berbamine can induce the apoptosis of human liver cancer cell line SMMC7721 and prostate cancer cell PC-3 cultured in vitro [Wang GY, et al.J Zhejiang Univ Sci B.2007; 8: 248-55; Chinese Journal of Experimental Surgery , 2007; 24 Vol. 8 No. 957-959]. It has also been reported that the berbamine derivative 4 ethoxybutyl berbamine [0-4-ethoxy-butyl-berbamine, referred to as EBB] can inhibit the growth of mouse liver cancer [Fang BJ, et al. World J Gastroenterol2004, 10: 950 -953] and induce apoptosis of human lung cancer cells cultured in vitro [Journal of Shanxi Normal University (Natural Science Edition) 2001 04 pp. 55-58]. However, these literature reports show that although berbamine hydrochloride or berbamine derivative EBB has a killing effect on tumor cells cultured in vitro, their anti-tumor effect in vivo is not ideal.

It is known that the water solubility of a compound is one of the key factors determining its bioavailability and efficacy. Most alkaloids are often combined with organic acids (citric acid, fruit acid, oxalic acid, succinic acid, acetic acid, propionic acid, etc.) to form highly water-soluble salts in plants. Berbamine or berbamine is currently commonly used Derivatives are hydrophobic alkaloids, insoluble in water. Berbamine hydrochloride prepared by using inorganic hydrochloric acid has low water solubility, less than 30mg/ml. The hydrophobicity of berbamine and the low water solubility of berbamine hydrochloride will undoubtedly affect its antitumor effect. Therefore, developing new berbamine salts to improve its water solubility and bioavailability may improve the antitumor effect of berbamine.

Contents of the invention

The object of the present invention is to provide a kind of novel berbamine organic acid salt (Berbamine citrate) with following general structure, the general structure of described berbamine organic acid salt berbamine citrate:

Wherein: R is citric acid monohydrate (C ₆ H ₅ O ₇ .H ₂ O), or anhydrous citric acid (C ₆ H ₅ O ₇ ).

Another object of the present invention is to provide the preparation method of above-mentioned berbamine citrate organic acid salt, realize through the following steps:

(1) At room temperature, add berbamine to R (citric acid monohydrate or anhydrous citric acid) solution for salt-forming reaction, the preferred weight ratio of berbamine and citric acid is but not limited to 4-20:1.

(2) Dry the above berbamine citrate salt solution to obtain light yellow or white berbamine citrate salt powder. Reaction formula:

  Berbamine Citric Acid Berbamine Salt

The method for preparing berbamine citrate used in the present invention has a high success rate, is simple and easy to implement, and has low cost, and is suitable for large-scale production (embodiment 1-2).

Another object of the present invention is to provide the application of the above-mentioned berbamine citrate salt in the preparation of anti-hematological neoplastic drugs. It involves but is not limited to the application in the preparation and treatment of leukemia, multiple myeloma, lymphoma and other drugs.

The prepared medicine is composed of curative effective dose of berbamine citrate and pharmaceutically acceptable adjuvants.

The prepared medicine also contains other antitumor medicines. The anti-hematological tumor drug combination of the berbamine citrate salt, for example, but not limited to, an anti-leukemia drug combination, an anti-multiple myeloma drug combination, an anti-lymphoma drug combination, and the like.

The main basis of the present invention is: berbamine commonly used at present is a kind of free alkaloid that does not form a salt, insoluble in water, or a kind of low water-soluble berbamine hydrochloride prepared with inorganic hydrochloric acid, and in fact, Most alkaloids are often combined with organic acids (citric acid, fruit acid, oxalic acid, succinic acid, acetic acid, propionic acid, etc.) in plants to form highly water-soluble organic acid salts to play a role. Therefore, the inventors of the present invention used the edible strong organic acid citric acid to design and prepare better water-solubility (Water-solubility) berbamine organic acid salts, and screened for anti-tumor activity in vitro and in animals, in order to obtain anti-tumor A new type of berbamine salt with higher activity and lower toxicity for further development into new drugs. Surprisingly, the inventors found that berbamine citrate not only has good water solubility, but also has good therapeutic effects on various blood tumor diseases in animals.

The characteristics of the berbamine citrate prepared by the above method are: the edible strong organic acid citric acid is used to replace the commonly used inorganic hydrochloric acid to prepare the berbamine salt, and the obtained berbamine citrate is not only water soluble High property, about 500mg/ml (see embodiment 3), is more than 16.6 times of berbamine hydrochloride (30mg/ml) commonly used at present, and the pH value of the solution prepared with above-mentioned berbamine citrate salt is between 4- Between 5, obviously higher than berbamine hydrochloride salt solution (pH value is about 2) (see embodiment 4).

The berbamine citrate of the present invention can selectively induce the death of various blood tumors such as leukemia, multiple myeloma, lymphoma and other tumor cells (see Examples 5-10). Animal experiments have confirmed that oral administration of berbamine citrate can significantly inhibit the growth of human xenograft tumors in animals, and some tumors, such as leukemia, have been completely eliminated, achieving a radical tumor effect, and the anti-tumor activity in vivo is significantly higher than that of berbamine hydrochloride Salt (see Example 11). More meaningfully, the results of animal experiments show that the berbamine citrate of the present invention has no obvious toxic reaction to experimental animals at an effective antitumor dose (see Example 11).

The medicine consists of the compound of general formula (I) of the present invention and optional pharmaceutical excipients or carriers allowed by the formulation.

The compounds of the present invention can be administered in oral forms such as but not limited to plain and enteric-coated tablets, capsules, pills, powders, granules, tinctures, solutions, suspensions and syrups. They may also be administered in parenteral forms such as, but not limited to, intravenous, intraperitoneal, subcutaneous and intramuscular forms well known to those of ordinary skill in the pharmaceutical arts.

Dosage regimens using the compounds of this invention are selected by those of ordinary skill in the art based on a variety of factors including, but not limited to, age, weight, sex, and physical condition of the recipient, severity of the disease requiring treatment, dosing route, the recipient's metabolism and excretory function, and the dosage form used.

The drug combination of the present invention may further comprise one or more anticancer drugs, such as existing anticancer drugs available in the market.

Anticancer drugs are often more effective when used in combination. In addition, it is best to administer the drug at the maximum tolerated dose for most drugs with the minimum amount of time between doses.

The compounds of the invention are preferably formulated with one or more pharmaceutically acceptable excipients prior to administration. Excipients are inert substances such as, but not limited to, carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, drug disintegrants, and encapsulating materials.

Another particular embodiment of the present invention is a pharmaceutical formulation comprising a compound of the present invention and one or more pharmaceutically acceptable excipients which are compatible with the other ingredients in the formulation and are Its recipients are harmless. The pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of a compound of the invention with one or more pharmaceutically acceptable excipients. In preparing the compositions of the present invention, the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be a capsule, sachet, wrapper or other container. The carrier may act as a diluent, which may be a solid, semi-solid or liquid material used as a carrier; or tablets, pills, powders, lozenges, suspensions, emulsions, solutions, syrups, soft and hard gel capsules , suppositories, sterile injectable solutions and sterile packaged powders.

For oral administration, the active ingredient may be combined with an oral, non-toxic pharmaceutically acceptable carrier such as, but not limited to, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, Calcium carbonate, calcium phosphate, calcium sulfate, methylcellulose, etc.; optionally combined with disintegrants, binders, lubricants, such as but not limited to: corn, starch, methylcellulose, Agar clay, xanthan gum, alginic acid, etc.; binders such as but not limited to gelatin, natural sugar, beta-lactose, corn sweetener, natural and synthetic rubber, gum arabic, carboxymethylcellulose, polyethylene glycol , paraffin, etc.; lubricants such as but not limited to: magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, etc.

In powder forms, the carrier can be a finely divided solid which is in admixture with the finely divided active ingredient. The active ingredient can be mixed with a carrier having binding properties in suitable proportions and compressed into the desired shape and size, thereby forming tablets. Said powders and tablets preferably contain from 1% to 99% by weight of the active ingredient which is the novel composition of the invention. Suitable solid carriers are carboxymethylcellulose magnesium, low melting beeswax and cocoa butter.

Sterile liquid preparations include suspensions, emulsions and syrups. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, a sterile organic solvent, or a mixture of sterile water and a sterile organic solvent.

The formulations described above can be presented in unit dosage form, which are physically discrete units containing unit dosages, suitable for administration to the human and other mammalian bodies. The unit dosage form can be a capsule or tablet, or a plurality of capsules or tablets. A "unit dose" is a predetermined quantity of an active compound of the invention calculated to produce the desired therapeutic effect, in combination with one or more excipients. The amount of a unit dose of active ingredient may be varied or adjusted from about 0.1 to about 1000 milligrams or more depending on the particular treatment involved.

Compared with currently commonly used berbamine and berbamine hydrochloride, berbamine citrate salt of the present invention has the following advantages and characteristics: (1) has better water solubility and is close to the pH value of human blood physiological state , is conducive to improving its bioavailability (embodiment 3-4); (2) the preparation process is simple and easy, and the cost is low, and is suitable for large-scale production (embodiment 1-2); (3) due to the use of edible organic acid Citric acid prepares berbamine salt, which has higher safety than the berbamine hydrochloride salt prepared by inorganic hydrochloric acid; (4) has wider and stronger antitumor activity, and it has been confirmed that sensitive hematological tumors have leukemia, Multiple myeloma, lymphoma, etc. (see embodiment 5-11); (5) toxicity is lower, and in vitro cell culture system and animal experiments confirm that berbamine citrate is effective to normal people under effective antitumor dosage. Cell growth and experimental animals have no obvious side effects (see Example 11).

Detailed ways:

The present invention is described further in conjunction with embodiment. It should be understood that the following examples are intended to illustrate the present invention without constituting any limitation to the scope of the present invention

Embodiment 1: preparation of berbamine citrate monohydrate

At room temperature, weigh 20 grams of berbamine, put it into a glass beaker, then add 200 milliliters of 2.5% citric acid monohydrate (C ₆ H ₅ O ₇ .H ₂ O) solution, stir until the berbamine is completely dissolved, the solution is completely transparent, and then the berbamine citrate salt solution is dried to obtain light yellow or white berbamine citrate crystals.

Reaction formula:

Berbamine Berbamine Citrate Monohydrate

Experimental results show: the berbamine citrate monohydrate salt prepared by applying this method not only has a high success rate (100%); moreover, the required reagents are few, only citric acid and water are needed, and the operation steps are few and simple, which is easy to use in ordinary laboratories. to operate.

Embodiment 2: preparation of anhydrous berbamine citrate

At room temperature, weigh 20 grams of berbamine, put it into a glass beaker, then add 200 milliliters of 2.5% anhydrous citric acid (C ₆ H ₅ O ₇ ) solution, stir until the berbamine is completely dissolved, and the solution is completely transparent, and then the berbamine citrate solution is dried to obtain slightly yellow or white berbamine citrate crystals.

  Berbamine           Berbamine Citrate Anhydrous Salt

Experimental results show: the anhydrous berbamine citrate salt prepared by applying this method not only has a high success rate (100%); moreover, the required reagents are few, only citric acid and water are needed, and the operation steps are few and simple, which is easy to use in ordinary laboratories. to operate.

Embodiment 3: Solubility comparison of berbamine citrate and berbamine hydrochloride

Weigh 0.1 g of berbamine citrate and berbamine hydrochloride respectively at room temperature, put them into 10ml test tubes, then slowly add deionized water, shake well while adding, until the added berbamine salt is fully dissolved , until the solution becomes completely transparent. Then, the water required to completely dissolve the berbamine salt was measured, and the solubility of the berbamine salt in water was calculated.

Experimental results show that: the solubility of berbamine citrate in water is about 500mg/ml, and the solubility of berbamine hydrochloride in water is about 30mg/ml. The water solubility of berbamine citrate is 16.6 times that of berbamine hydrochloride.

Embodiment 4: berbamine citrate salt and berbamine hydrochloride salt solubility pH value comparison

Weigh 0.1 g of berbamine citrate and berbamine hydrochloride respectively at room temperature, put them into 10ml test tubes, then slowly add deionized water, shake well while adding, until the added berbamine salt is fully dissolved , until the solution becomes completely transparent (2ml of water). Then, measure the pH value of the solution with precision pH test paper.

The experimental results show that the pH value of the berbamine citrate saline solution is about 4.5, while the pH value of the berbamine hydrochloride saline solution is about 2.0. Compared with the pH value of the berbamine hydrochloride saline solution, the pH value of the berbamine citrate saline solution is closer to the normal blood physiological pH value (7.3-7.4).

Example 5: Determination of anti-human chronic myeloid leukemia cell K562 activity of berbamine citrate

(1) Experimental materials

Leukemia cell line: Human K562 leukemia cell line was purchased from Shanghai Cell Bank, Chinese Academy of Sciences.

Main reagents: berbamine citrate is synthesized by ourselves.

Main instruments: cell incubator, microplate reader

(2) Experimental method

Take 8,000 well-grown leukemia cells and inoculate them into wells of a 96-well cell culture plate. The culture medium is 1640 cell culture medium containing 10% fetal bovine serum. Drugs of different concentrations were added, mixed evenly, and placed in a carbon dioxide (5% CO2) cell incubator at 37° C. for 48 hours. The concentration of viable cells was then determined by the MTT method. In this experiment, the cell viability of the control group (without drug treatment) was set as 100%, and the cell viability (%) and the 48-hour half-inhibitory concentration of leukemia cells (48-hour IC50 value) were calculated after drug action.

(3) Experimental results

The experimental results prove that berbamine citrate can rapidly induce the death of human leukemia cell line K562 cells and inhibit the growth of leukemia cells, and its 48-hour leukemia cell half growth inhibitory concentration (48-hour IC50) is about 4.0 μg/ml.

Example 6: Determination of anti-NB4 activity of berbamine citrate salt in human acute myeloid leukemia cells

(1) Experimental materials

Leukemia cell line: Human NB4 leukemia cell line was purchased from Shanghai Cell Bank of Chinese Academy of Sciences.

Main reagents: berbamine citrate is synthesized by ourselves.

Main instruments: cell incubator, microplate reader

(2) Experimental method

Take 8,000 well-grown leukemia cells and inoculate them into wells of a 96-well cell culture plate. The culture medium is 1640 cell culture medium containing 10% fetal bovine serum. Add different concentrations of berbamine citrate, mix well, and culture in a carbon dioxide (5% CO2) cell incubator at 37° C. for 48 hours. The concentration of viable cells was then determined by the MTT method. In this experiment, the cell viability of the control group (without drug treatment) was set as 100%, and the cell viability (%) and the 48-hour half-inhibitory concentration of leukemia cells (48-hour IC50 value) were calculated after drug action.

(3) Experimental results

The experimental results prove that berbamine citrate can induce the death of human acute myeloid leukemia cell line NB4 cells and inhibit the growth of leukemia cells.

Example 7: Determination of K562/ADR activity of berbamine citrate against drug-resistant human chronic myeloid leukemia cells

(1) Experimental materials

Leukemia cell line: The multidrug-resistant human K562/ADR leukemia cell line was provided by the Cancer Institute of Zhejiang University.

Main reagents: berbamine citrate is synthesized by ourselves.

Main instruments: cell incubator, microplate reader

(2) Experimental method

Take 8,000 well-grown leukemia cells and inoculate them into wells of a 96-well cell culture plate. The culture medium is 1640 cell culture medium containing 10% fetal bovine serum. Drugs of different concentrations were added, mixed evenly, and placed in a carbon dioxide (5% CO2) cell incubator at 37° C. for 48 hours. The concentration of viable cells was then determined by the MTT method. In this experiment, the cell viability of the control group (without drug treatment) was set as 100%, and the cell viability (%) and the 48-hour half-inhibitory concentration of leukemia cells (48-hour IC50 value) were calculated after drug action.

(3) Experimental results

The experimental results prove that berbamine citrate can induce the death of drug-resistant human leukemia cell line K562 and inhibit the growth of leukemia cells, and its 48-hour leukemia cell half growth inhibitory concentration (48-hour IC50) is about 8.0 μg/ml.

Example 8: Determination of Jurkat activity of berbamine citrate salt against human lymphoid leukemia cells

(1) Experimental materials

Human leukemia cell line: human lymphocytic leukemia cell line Jurkat was purchased from Shanghai Cell Bank, Chinese Academy of Sciences.

Main reagents: berbamine citrate is synthesized by ourselves.

Main instruments: cell incubator, microplate reader

(2) Experimental method

Take 8,000 well-grown leukemia cells and inoculate them into wells of a 96-well cell culture plate. The culture medium is 1640 cell culture medium containing 10% fetal bovine serum. Drugs of different concentrations were added, mixed evenly, and placed in a carbon dioxide (5% CO2) cell incubator at 37° C. for 48 hours. The concentration of viable cells was then determined by the MTT assay. In this experiment, the cell viability of the control group (without drug treatment) was set as 100%, and the cell viability (%) and the 48-hour half-inhibitory concentration of leukemia cells (48-hour IC50 value) were calculated after drug action.

(3) Experimental results

The experimental results prove that berbamine citrate can induce the death of human lymphocytic leukemia cell line Jurkat and inhibit the growth of leukemia cells, and its 48-hour leukemia cell half growth inhibitory concentration (48-hour IC50) is about 3.32 μg/ml.

Example 9: Determination of anti-human multiple myeloma cell RPM18226 activity of berbamine citrate

(1) Experimental materials

Human multiple myeloma cell line: the human multiple myeloma cell line RPM18226 was provided by the Institute of Blood Diseases, Zhejiang University.

Main reagents: berbamine citrate is synthesized by ourselves.

Main instruments: cell incubator, microplate reader

(2) Experimental method

Take 8000 well-grown human multiple myeloma cell line RPM18226 cells and inoculate them into wells of a 96-well cell culture plate. The culture medium is 1640 cell culture medium containing 10% fetal bovine serum. Drugs of different concentrations were added, mixed evenly, and placed in a carbon dioxide (5% CO2) cell incubator at 37° C. for 48 hours. The concentration of viable cells was then determined by the MTT method. In this experiment, the cell viability of the control group (without drug treatment) was set as 100%, and the cell viability (%) and the 48-hour half-inhibitory concentration of leukemia cells (48-hour IC50 value) were calculated after drug action.

(3) Experimental results

The experimental results prove that berbamine citrate can induce cell death of human multiple myeloma cell line RPM18226, and its 48-hour half growth inhibitory concentration (48-hour IC50) is about 8.0 μg/ml, indicating that berbamine citrate has anti-multiple myeloma myeloma activity.

Example 10 Determination of DOHH2 activity of berbamine citrate salt against human lymphoma cells

(1) Experimental materials

Human lymphoma cell line: The human lymphoma cell line was provided by Dr. Wu Dong, Department of Hematology, Second Affiliated Hospital, Zhejiang University School of Medicine.

Main reagents: berbamine citrate is synthesized by ourselves.

Main instruments: cell incubator, microplate reader

(2) Experimental method

Take 8,000 well-grown leukemia cells and inoculate them into wells of a 96-well cell culture plate. The culture medium is 1640 cell culture medium containing 10% fetal bovine serum. Drugs of different concentrations were added, mixed evenly, and placed in a carbon dioxide (5% CO2) cell incubator at 37° C. for 48 hours. The concentration of viable cells was then determined by the MTT method. In this experiment, the cell viability of the control group (without drug treatment) was set as 100%, and the cell viability (%) and the 48-hour half-inhibitory concentration of leukemia cells (48-hour IC50 value) were calculated after drug action.

The experimental results prove that berbamine citrate can induce the death of human lymphoma cells, and its 48-hour half growth inhibitory concentration (48-hour IC50) is about 2.0 μg/ml, indicating that berbamine citrate has anti-human lymphoma cell activity.

Example 11: Comparison of the effects of berbamine citrate and berbamine hydrochloride on xenograft tumor growth and animal toxicity in human leukemia K562/ADR nude mice

(1) Experimental materials

Experimental animals: Nude mice were purchased from Shanghai Animal Center, Chinese Academy of Sciences

Reagents: Berbamine citrate was synthesized by ourselves, and Berbamine hydrochloride was purchased from Chengdu Julong Natural Pharmaceutical Life Technology Co., Ltd.

Instrument: cell incubator

(2) Experimental method

Take 7-week-old nude mice and subcutaneously inoculate human leukemia cells K562 5 x 10 ⁷ /mouse on their backs. After 24 hours, they were randomly divided into 3 groups. Medication group: the berbamine citrate and berbamine hydrochloride groups were administered orally, at a dose of 100 mg per kilogram of body weight, 3 times a day (infusion). Control group: replaced by normal saline, used continuously for 10 days. A total of 30 days were observed, during which the tumor weight, body weight, activity and diet of the nude mice were measured. At the end of the experiment, the mice were sacrificed, and the tumor tissues were taken to measure the actual weight.

(3) Experimental results

The experimental results prove that berbamine citrate has a significant inhibitory effect on the growth of xenograft tumors in human leukemia nude mice. During the 45-day experimental period, 6 nude mice inoculated with tumor cells were treated with berbamine citrate, and no tumor grew. , the tumor-free rate reached 100% (6/6), while in the berbamine hydrochloride group, 3 of the 6 nude mice had tumor growth, the average tumor weight reached 4.67 grams, and the tumor-free rate was 50% (3/6) . All 7 nude mice in the control group showed obvious tumor growth, the tumor formation rate was 100% (7/7), and the average tumor weight was 7.22 grams. The average body weight of the nude mice in the berbamine citrate group was 19.81 grams, and the average body weight of the nude mice in the berbamine hydrochloride group was 16.87 grams. These experimental results show that the antitumor activity of berbamine citrate in animals is significantly better than that of berbamine hydrochloride, and its toxicity is also significantly lower than that of berbamine hydrochloride.

Claims (8)

1. lemon acid berbamine salt, the general formula of described lemon acid berbamine salt is (I):

Wherein

R is water citric acid or Citric Acid, usp, Anhydrous Powder.

2. preparation method who prepares the described lemon acid berbamine salt of claim 1 is characterized in that realizing by following steps:

(1) under the room temperature, Berbamine is added water citric acid or Citric Acid, usp, Anhydrous Powder solution is carried out to reactant salt, the weight ratio of Berbamine and citric acid is 4～20:1;

(2), get little yellow or white lemon acid berbamine salt powder with above-mentioned lemon acid berbamine salt solution drying;

Reaction formula:

3. the application of formula according to claim 1 (I) lemon acid berbamine salt in preparation treatment neoplastic hematologic disorder disease medicament.

4. application according to claim 3 is characterized in that: the application in the leukemic medicine of preparation treatment.

5. application according to claim 3 is characterized in that: the application in the medicine of preparation treatment multiple myeloma.

6. application according to claim 3 is characterized in that: the application in the lymphadenomatous medicine of preparation treatment.

7. application according to claim 3 is characterized in that: described medicine is formed by containing the lemon acid berbamine salt for the treatment of significant quantity and preparation allowable pharmaceutical excipients or carrier.

8. application according to claim 3 is characterized in that: drug prepared also contains other antitumor drugs.